By Joseph F. John, Jr., MD

Clinical Professor of Medicine and Microbiology, Medical University of South Carolina, and Lowcountry Infectious Diseases, Charleston

Dr. John reports no financial relationships relevant to this field of study.

SYNOPSIS: Investigators examined the mechanism that allows Moraxella catarrhalis to persist in some patients with COPD.

SOURCE: Murphy TF, Brauer AL, Pettigrew MM, et al. Persistence of Moraxella catarrhalis in chronic obstructive pulmonary disease and regulation of Hag/MID adhesin. J Infect Dis 2019;219:1448-1455.

Dr. Tim Murphy in Buffalo has been working on the microbiology of symptomatic pulmonary disease for many years. Here is the latest and greatest installment from a cohort of adults with COPD studied prospectively over the past 20 years. Over the years, Murphy and colleagues have discovered that one of the major bacterial pathogens in COPD, Moraxella catarrhalis, has a variability of duration of colonization. What allows this organism to colonize and then persist in some COPD patients and not in others? The reason for the variability has been unknown. In this paper, Murphy et al noted that one of the major adhesins, Hag/MID (in its expression and then disappearance), explains the persistence of M. catarrhalis.

Between 1994 and 2014, patients with COPD were seen every month. An exacerbation caused by M. catarrhalis was considered to be the onset of new clinical symptoms and the acquisition of a new strain of M. catarrhalis. Investigators studied the genetic characteristics of the Hag/MID gene in persistent and cleared strains. Researchers also studied adherence to human epithelial cells and expression of the Hag/MID protein for the persistent and cleared strains. Earlier studies had shown that Hag/MID mediates adherence of the bacterium to respiratory epithelial cells, one of the virulence phenotypes. When Hag/MID is expressed, the bacterium shows aggregation when grown in brain heart infusion broth, a second virulence phenotype.

The major finding of the study was that most strains that expressed Hag/MID on acquisition in COPD patients ultimately lost that expression during persistence. The authors went on to study the mechanism of the loss of Hag/MID expression. In five persistent strains, the Hag/MID gene had one of two different genetic changes. One was an out-of-frame mutation; thus, the protein was not expressed. Another mode of dysregulation was caused by slipped-strand mispairing through changes in a polynucleotide repeat near the start codon in the open reading frame. The impact of the loss of Hag/MID was studied further with regard to virulence phenotypes. Loss of the protein resulted in decreased adherence to respiratory epithelial cells and loss of aggregation.


An adhesion molecule aids a bacterium to inhabit an abnormal respiratory tract initially, perhaps causing a frank exacerbation of bronchitis. Then, for it to persist, it loses the very adhesin that aided its initial colonization. Why does the bacterium even care to make this small genetic change that results in a radical change in protein expression (in this case, a protein that is related to virulence)? The paradox may reside mainly in the concept that pathogens in COPD do not want to kill the host. In the case of the COPD patient, the host houses an immense surface area of respiratory epithelium that offers a sanctuary if the bacterium can reside relatively peacefully. Entry is the first order for M. catarrhalis, but guaranteed survival in a demanding environment is paramount. Indeed, in this study, Hag/MID continued to be expressed in 28 of 30 strains that were cleared, whereas only 17 of 30 strains that were persistent continued to express the protein. The longer the persistence, the less likely it was that Hag/MID would be expressed. Hag/MID is a multifunctional autotransporter. Why would its persistence be facilitated by its absence?

Hag/MID elicits an immune response, both mucosal and systemic. Perhaps these responses select the Hag/MID-negative phenotype, allowing the organism to escape some immune control. Analogously, there are prospects for immunization with Hag/MID. Vaccines may reduce initial colonization with M. catarrhalis, an apparent advantage for the COPD patient. Enter the airway microbiome, the last consideration in this paper. Clearly, compared to the airway microbiome in healthy people, the airway microbiome in COPD patients contains several pathogens, including M. catarrhalis. Even the COPD airway has to come to some equilibrium. In that sense, the downregulation of Hag/MID serves an equilibrium of the microbiome even in the altered pulmonary airway. This work by Murphy et al shows the complexity of the bacterial pathogens’ flux into and out of the pulmonary environment. One of these pathogens, M. catarrhalis, is well armed to invade this environment, but once there, is happy to downregulate its virulence.

This research group may have discovered a trait of some pathogens to invade but, once established in a milieu, to use genetic mechanisms to modify its protein expression to become part of the microbial background.